Fucoidan hair growth agent

ABSTRACT

To develop a novel administration method of a fucoidan-containing hair-growing agent and to provide a means for exerting excellent effects of a fucoidan. 
     A hair-growing agent of the present invention is characterized in that it is composed of a combination of a fucoidan-containing microneedle and a fucoidan-containing liniment. A base of the fucoidan-containing microneedle is preferably a biosoluble polymer. A hair-growing method of the present invention is characterized in that the fucoidan-containing microneedle and the fucoidan-containing liniment are concomitantly used.

TECHNICAL FIELD

The present invention relates to a hair-growing agent composed mainly offucoidan.

BACKGROUND ART

Fucoidan is a kind of acidic polysaccharide polymers containing fucosesulfate as a main constituent sugar. Fucoidan is a viscous componentcontained in brown algae such as Undaria pinnatifida, Cladosiphonokamuranus and tangle weed, and is known to have a hair-growing effect.

In relation to the hair-growing effect of fucoidan, a hair-growingcomposition containing fucoidan (Patent Document 1), a cosmeticcontaining fucoidan or a decomposed product thereof and having ahair-growing effect (Patent Document 2), foods and drinks containingfucoidan and having a hair-growing effect (Patent Document 3), a factthat a high-molecular-weight fucoidan having an average molecular weightof 1,000,000 or more is relatively effective for hair growth (PatentDocument 4), an oral hair-growing agent with a combination of fucoidanand a seaweed-derived protein (Patent Document 5), a hair-growing agentcontaining fucoidan and a soybean protein (Patent Document 6), ahair-repairing agent obtained by blending propolis and the like intofucoidan (Patent Document 7) have already been published. All of themare oral agents or liniments.

However, it is well known that even if a drug is orally administered,the drug is not necessarily delivered to a site of a body where aneffect of the drug is expected to be exerted, and the utilization rateof the oral drug is low in many cases. Also, it is well known that evenif the drug is applied to a particular site of the body, a corneum actsas a barrier to drug penetration, and the drug does not sufficientlypenetrate merely by applying the drug to the body surface. Inparticular, an efficiency of percutaneously absorbing ahigh-molecular-weight drug is extremely low, and it is difficult toexert effects only by absorption from the skin. Fucoidan is an acidicpolysaccharide polymer, its percutaneous absorbability is extremely low,and only a minute amount thereof is absorbed through pores.

Thus, the oral administration method and the application method have aproblem of inefficient drug use.

On the other hand, the application method can remarkably improve theefficiency of penetrating the drug by perforating a corneum using aminute needle i.e. a microneedle.

An item in which a lot of the microneedles are accumulated on asubstrate is called a microneedle array. In addition, a product which ismade easier to use by adding an adhesive tape for attaching themicroneedle array to a skin, a covering sheet for keeping a sterilestate until use, and the like to the microneedle array, is called amicroneedle patch. Herein, the tape refers to a film, cloth or papercoated with an adhesive.

Although many attempts have already been made to transdermallyadminister a drug using such a microneedle, its use as a hair-growingagent seems not to have yet been reported.

The microneedle can be prepared using a water-insoluble material such asstainless steel and polylactic acid, but a microneedle made of a base(biosoluble polymer base) which dissolves by water in a body such ascarbohydrate as a substrate can facilitate intradermal and subcutaneousadministration of a drug by previously blending the drug into themicroneedle, because the injected microneedle dissolves in the body.Herein, the substrate refers to a main component constituting themicroneedle.

The microneedle array made of the biosoluble polymer substance is oftenmanufactured using a mold. A microneedle pattern is formed bylithography using a photosensitive resin, followed by transferring, toprepare a mold having recesses for forming microneedles. A microneedlematerial is cast on this mold, subsequently heated to evaporatemoisture, and then the solidified material is released from the mold toobtain a microneedle array.

PRIOR ART DOCUMENTS Patent Documents Patent Document 1: Japanese PatentApplication Laid-Open No. 2003-155218 Patent Document 2: Re-publicationof WO 01/039731 Patent Document 3: Japanese Patent Application Laid-OpenNo. 2005-281277 Patent Document 4: Japanese Patent Application Laid-OpenNo. 2007-262036 Patent Document 5: Japanese Patent Application Laid-OpenNo. 2008-169140 Patent Document 6: Japanese Patent Application Laid-OpenNo. 2009-114170 Patent Document 7: Japanese Patent Application Laid-OpenNo. 2014-218440 SUMMARY OF INVENTION Problem to be Solved

In a hair root area inside a scalp, there are hair bulbs distributed inthe dermic layer having a thickness of 0.5 to 1.5 mm, and hair grows byhair matrix cells inside the hair bulbs. Although a hair-growing agentshould be delivered to the dermic layer, its skin penetration isprevented by a corneum barrier, and this is why there are fewcommonly-effective percutaneous hair-growing agents. The object of thepresent invention is to develop a novel administration method of thefucoidan-containing hair-growing agent and to provide a means forexerting excellent effects of fucoidan.

Solution to Problem

The present inventors have continued examinations with hope for theadministration through the microneedles exerting a hair-growing effectfar superior to that of the conventional liquid administration, and thisexaminations have led to the present invention. The hair-growing agentaccording to the present invention made in order to solve the aboveproblems is characteristically obtained by combining afucoidan-containing microneedle and a fucoidan-containing liniment.

In the present invention, it was found that although administration offucoidan is effective even by administering the fucoidan-containingmicroneedle alone, the effect is further enhanced by combining thefucoidan-containing microneedle with a fucoidan-containing liquid(essence). Even only the fucoidan-containing microneedle expresses ahair-growing effect far superior to that in application of thefucoidan-containing essence to skin. Furthermore, concomitant use(combination) of both expresses a more excellent effect, which is afeature of the present invention. Although the mechanism remainsunclear, it is considered that the mechanism is attributed to thepercutaneous penetration of fucoidan contained in the microneedlesthrough skin pores formed by the microneedles, and furthermore to theenhanced intradermal penetration of fucoidan contained in the liquid.

That is, the hair-growing method of the present invention ischaracterized in that the hair-growing effect is enhanced by combiningadministration of the fucoidan-containing microneedles andadministration of the fucoidan-containing microneedles andfucoidan-containing liquid. As for the timing of concomitant use, themicroneedles and the liquid may be simultaneously administered, or eachof them may be administered at another time.

The length of the fucoidan-containing microneedle is suitably 0.1 to 1.5mm. A more suitable length is 0.15 to 1.0 mm. If the length is 0.1 mm orless, the function as a microneedle cannot be sufficiently exhibited. Ifthe length is 1.0 mm or more, the effect is sufficient, but pain due toadministration is accompanied, causing problems on a user's compliance.As a base for the microneedle containing fucoidan, a water-solublepolymer is desirable. A biosoluble polymer such as hyaluronic acid,collagen, hydroxypropyl cellulose and chondroitin sulfate isparticularly preferred, because skin moisture diffuses in the needlepart within a short period after its insertion and the needle partinserted into the skin swells and then dissolves.

As a fucoidan-containing liniment, not only the liquid but also a cream,a mousse, a gel, etc. can be used in combination with a microneedlemethod. The amount of fucoidan blended in the hair-growing agent variesdepending on the dosage form, administration method, desired effect,treatment period, etc. and so cannot be unconditionally defined.However, it is appropriate that its concentration in the liquid or thecream is typically 0.1 μg/mL to 100 mg/mL. Additionally, in themicroneedle preparation, one dose is blended into one or severalmicroneedle arrays, and the dose is suitably 0.1 μg to 2 mg per onemicroneedle array.

In the hair-growing agent, other hair-growing promoters can be added inorder to complement or enhance its hair-growing activity. For example,minoxidil, carpronium chloride, t-flavanone, adenosine,6-benzylaminopurine, pentadecanoic acid glyceride, crude drug extractand the like are suitable.

In addition to the hair-growing promoter, if necessary, a plant extract,an aqueous component, a moisturizer, a thickener, a preservative, anantioxidant, a perfume, a coloring material, a drug and the like whichare approved as a drug, a cosmetic, a quasi drug, a pharmaceutical andthe like may be appropriately blended into the hair-growing agent, aslong as the purpose and the effect of the hair-growing agent are notimpaired.

The plant extract includes red pepper, aloe, tea leaf, magnolia flower,Japanese horseradish, Ligustrum lucidum fruit, spilanthes acmella,gardenia, asiasarum sieboldii, garlic, mint, coix seed, Daemonoropsdraco, burdock, licorice, gynostemma pentaphyllum, Ganoderma lucidum,rehmannia root, monoammonium glycyrrhizinate, glycyrrhetinic acid,glycyrrhizin, sesame, cnidium rhizome, polygonum root, rumex root,carrot, ginger tincture and the like, and each of them can be used aloneor in combination of plural kinds.

Effects of Invention

The fucoidan-containing microneedle of the present invention can exert agreater effect than in a case of using the conventional liniment alone.

Furthermore, by combining the fucoidan-containing microneedleadministration and the fucoidan-containing liniment administration, thehair-growing effect can be greater than in a case of using either one ofthem alone.

The hair-growing agent of the present invention can be used as anypreparation which is widely usable for pharmaceuticals, quasi-drugs,cosmetics and the like.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates a figure showing a method for manufacturing afucoidan-containing microneedle array.

FIG. 2 illustrates a figure showing comparison of effects of variousadministration methods for the hair-growing agent of this patentapplication, and comparison of effects in combination with otherhair-growing agents. In the figure, the ordinate represents an amount ofthe grown hair (mg/cm²).

FIG. 3A illustrates a photograph of a head showing a hair-growing effectof a panelist in hair growth test 3.

FIG. 3B illustrates a photograph of a head showing a hair-growing effectof another panelist in hair growth test 3.

FIG. 4 illustrates graphs showing a questionnaire result regarding useof the hair-growing agent on the panelists after completion of hairgrowth test 3.

FIG. 5 illustrates graphs showing evaluations regarding hair restorationand hair loss on the panelists after completion of hair growth test 3.

FIG. 6 illustrates a graph showing effects perceived by the panelistsafter completion of hair growth test 3.

DESCRIPTION OF EMBODIMENTS

Hereinafter, embodiments of the present invention will be explained onthe basis of Examples. However, the present invention is not limited tothe contents of Examples.

As fucoidan of the present invention, a product purified fromCladosiphon okamuranus was used. For this product, a commercial product(LIMUVEIL, made by TANGLEWOOD K.K.) can be used.

(Hair Growth Test 1)

A microneedle pattern having a predetermined shape was formed as shownin FIG. 1 by a lithography method of irradiating a photosensitive resinwith light. This microneedle pattern was electroformed to form a mold 10having microneedle-forming recesses 11 onto which the pattern had beentransferred. The microneedle-forming recesses 11 have a stratovolcanoshape with a root diameter of 200 μm and a depth of 300 μm, arranged ina lattice pattern at an interval of 600 μm, and 280 recesses are formedper 1 cm². A microneedle array 12 was molded using the recessed mold forformation of the present invention.

5 g of hyaluronic acid (FCH-80, derived from culture, made by KikkomanBiochemifa Company) and 5 g of LIMUVEIL HV (aqueous solution containing1.2% of fucoidan, made by TANGLEWOOD K.K.) were added to 90 g of waterto prepare a homogeneous solution. The aqueous solution was cast on themold 10, dried at room temperature for 24 hours, and released from themold to obtain a microneedle array sheet. This sheet was cut to obtain amicroneedle array having a diameter of 1 cm. A content of fucoidan perone microneedle array was 25 μg.

0.1 g of LIMUVEIL HV was dissolved in 200 g of water to prepare afucoidan-containing extract.

The following animal experiment was carried out in an animal testlaboratory of Kyoto Pharmaceutical University in compliance with theoperative provision for animal experiment in Kyoto PharmaceuticalUniversity (rule of Kyoto Pharmaceutical University in consideration ofviewpoints of science, animal welfare and environmental conservation,and health and safety of persons engaged in animal experiment and thelike, on the basis of basic guideline on implementation of animalexperiment and the like at research institutes and the like (PublicNotice of the Ministry of Education, Sports, Culture, Science andTechnology No. 71, in 2006)).

Male C3H/HeN mice (CHARLES RIVER LABORATORIES JAPAN, INC.) werepreliminarily raised, and at 6 weeks of age, their backs were sheared bya hair-clipper, and furthermore shaved with a razor for using the micein the experiment.

A fucoidan-containing microneedle (fMN) and a fucoidan-containingextract (fEX) were administered at a predetermined time interval for 22days, and after 24 days, an amount of grown hair was measured.

In relation to the single dose, in the case of the microneedle, onepatch is applied, and in the case of the inclusion-type extract, 50 μLof the extract was applied on an area of about 1 cm². In both cases, theamounts of fucoidan were the same, 25 μg. The results are summarized inTable 1. From Table 1, it can be found that the concomitant use of thefucoidan-containing microneedle and the fucoidan-containing extract isexcellent in hair-growing effect.

In the hair growth test, the alternate-day administration refers to anaspect that the fMN was administered on the first day and the fEX wasadministered on the next day, and this cycle of the fMN and fEX wascontinued 11 times for 22 days. The administration of 2 days out of 3days refers to an aspect that the fMN was administered on the first day,the fEX was administered on the second day and administration wassuspended on the third day, and this cycle was continued 8 times for 23days. Note that, when the hair-growing agent to be administered was onekind, the agent was administered on the first and second days, andadministration was suspended on the third day, and this cycle wasrepeated 8 times (16 applications), which refers to administrationcontinued for a total of 23 days.

TABLE 1 Hair growth test result administered hair- interval of amount ofthe test number growing agent administration grown hair Example 1 fMN +fEX alternate-day 0.7 Example 2 fMN + fEX 2 days out of 3 days 0.6Comparative fMN 2 days out of 3 days 0.3 Example 1 Comparative fEX 2days out of 3 days 0.1 Example 2 Comparative not administered 0 Example3 Reference commercial product alternate-day 0.2 Example 1A unit of the amount of the grown hair is mg/cm².The commercial product in the Reference Example is a 5% minoxidilaqueous solution (Taisho Pharmaceutical Co., Ltd.).

(Hair Growth Test 2)

The hair-growing effects were compared using fucoidan-containing extractas a main active ingredient in various administration methods. In thesame manner as in the hair growth test 1, C3H/HeN mice were sheared andshaved.

The administered drugs and administration methods are summarized inTable 2. After 40 days, grown hair was shaved off, washed, dried, andits weight was measured in order to quantitate the hair growth state.

The administered drug was somewhat different from that in the hairgrowth test 1. The microneedle array (MN) was not blended with only 5 gof LIMUVEIL HV in the hair growth test 1, but 1 g of carrot extract(MARUZEN PHARMACEUTICALS CO., LTD.) and 1 g of ginger tincture (MARUZENPHARMACEUTICALS CO., LTD.) were added to 5 g of LIMUVEIL HV. The methodof manufacturing the microneedle array is the same as in the hair growthtest 1.

As a liniment, a LIMUVEIL liquid (LQ) was used. A fucoidan contenttherein did not correspond to 0.1 g of LIMUVEIL HV in the hair growthtest 1, but corresponded to 0.02 g of carrot extract (MARUZENPHARMACEUTICALS CO., LTD.) and 0.02 g of ginger tincture (MARUZENPHARMACEUTICALS CO., LTD.) in addition to 0.1 g of LIMUVEIL HV, and theproduction method for the liniment was exactly the same as in the test1.

For both MN and LQ, the doses were 25 μg in terms of fucoidan. For thereference example (commercial product), a 5% minoxidil aqueous solution(RiUP) (X) was used, and its dose was 40 μL.

The administration cycle of each preparation in the hair growth test isshown in Table 2, and the result of the amount of the grown hair 40 daysafter administration is shown in FIG. 2. A unit of the amount of thegrown hair is mg/cm².

TABLE 2 Administration schedule day aspect 1 2 3 4 5 6 7 8 9 10 11 12 13only LQ (1) LQ LQ LQ LQ LQ LQ only MN (1) MN MN MN MN MN MN only LQ (2)LQ LQ LQ LQ LQ LQ LQ LQ LQ LQ LQ LQ only MN (2) MN MN MN MN MN MN MN MNMN MN MN MN LQ + MN (1) MN MN LQ MN MN LQ MN MN MN MN LQ LQ + MN (2) MNLQ MN LQ MN LQ MN LQ MN LQ MN LQ LQ + MN (3) MN LQ LQ MN LQ LQ MN LQ LQMN LQ LQ commercial product X X X X X X

From the results in Table 2 and FIG. 2, it was found that it wasextremely effective to alternately administrate the microneedle and theliquid as the administration method of fucoidan. In relation to theadministration program, it could be confirmed that thefucoidan-containing extract was optimal as the main valuable component,and concomitant administration of the microneedle application and theliquid was more effective.

(Hair Growth Test 3)

Volunteers were tested at a specialized agency where efficacies ofcosmetics and quasi drugs were evaluated. Informed consent was obtainedfrom each volunteer subject, and various tests were implemented. Theoutline of the implementation was as follows.

1. Panelists: 4 males (48 to 57 years old), 8 females (47 to 59 yearsold)2. Test period: 12 weeks

3. How to use

The hair-growing needle and the hair-growing liniment were the same asthose used in Example 2.

Number of applications of the hair-growing needle: 3 times/week

Number of applications of the hair-growing liniment: morning/night use

4. Evaluation of effect

The effect was judged by head photographs between before and 12 weeksafter the use. Two representative examples out of 12 subjects are shown.After 12 weeks, in the heads of the two panelists, increase of hairaround the area on which the hair-growing needle had been pasted wasremarkably observed with the naked eye (FIGS. 3A and 3B).

Evaluation results and questionnaire results of 12 panelists are shown(FIGS. 4 to 6). In relation to the use of the hair-growing agent of thepresent invention, two-thirds of panelists were satisfied, and 80% ormore of panelists indicated willingness to continue to use it (FIG. 4).In relation to the decrease of hair loss and increase of hair, themajority of panelists perceived its effect (FIG. 5), and it isconsidered that the panelists who perceived the effect and the panelistswho expect future effects expressed their intention to continue the use.Moreover, in addition to the decrease of hair loss and the hair growth,effects such as increased hair thickness, volume-up of hair, increasedfirmness and resilience of hair and decreased white hair are alsoperceived, and it was found that 87% of the panelists perceived anyadvantageous effect for hair (FIG. 6). 13% of panelists answered thatthere was no effect, but no adverse effect on hair was observed.

1. A hair-growing agent composed of a combination of afucoidan-containing microneedle and a fucoidan-containing liniment. 2.The hair-growing agent according to claim 1, wherein a base of thefucoidan-containing microneedle is a biosoluble polymer.
 3. Thehair-growing agent according to claim 1, wherein the fucoidan in thefucoidan-containing microneedle and the fucoidan-containing liniment isderived from a brown alga.
 4. The hair-growing agent according to anyone of claims 1 to 3, further containing a carrot extract and a gingertincture as a drug.
 5. A hair-growing method (excluding medicalpractice), wherein the fucoidan-containing microneedle and thefucoidan-containing liniment are concomitantly used.
 6. A hair-growingagent composed of a fucoidan-containing microneedle alone.